BRCA1基因185delAG突变抑制人卵巢表面上皮细胞中Akt依赖的、IAP介导的半胱天冬酶3失活。

BRCA1 185delAG mutation inhibits Akt-dependent, IAP-mediated caspase 3 inactivation in human ovarian surface epithelial cells.

作者信息

Johnson Nicole C, Dan Han C, Cheng Jin Q, Kruk Patricia A

机构信息

University of South Florida College, Tampa 33612, USA.

出版信息

Exp Cell Res. 2004 Aug 1;298(1):9-16. doi: 10.1016/j.yexcr.2004.04.003.

DOI:10.1016/j.yexcr.2004.04.003

PMID:15242757

Abstract

BRCA1 mutations have long been associated with altered apoptosis. We have recently reported that caspase 3 activation is increased in human ovarian surface epithelial (OSE) cells expressing a germline N-terminal BRCA1 185delAG mutation. Here, we report increased caspase 3 activity in 185delAG OSE cells associated with decreased expression of cIAP-1 and X-linked inhibitor of apoptosis (XIAP), and decreased ubiquitination of caspase 3. Overexpression of XIAP restored active caspase 3 ubiquitination and lowered levels of caspase 3 activity. Further, the BRCA1 185delAG mutation was associated with reduced levels of phosphorylated Akt1. Transfection with activated Akt1 led to increased cIAP-1 and XIAP levels similar to that seen in BRCA1 185delAG cell lines. Taken together, these data suggest a direct link between the BRCA1 185delAG mutation and alterations in the caspase-mediated apoptotic pathway.

摘要

BRCA1突变长期以来一直与细胞凋亡改变有关。我们最近报道，在表达种系N端BRCA1 185delAG突变的人卵巢表面上皮（OSE）细胞中，半胱天冬酶3的激活增加。在此，我们报告185delAG OSE细胞中半胱天冬酶3活性增加，这与细胞凋亡抑制蛋白1（cIAP-1）和X连锁凋亡抑制蛋白（XIAP）表达降低以及半胱天冬酶3的泛素化减少有关。XIAP的过表达恢复了活性半胱天冬酶3的泛素化并降低了半胱天冬酶3的活性水平。此外，BRCA1 185delAG突变与磷酸化Akt1水平降低有关。用激活的Akt1转染导致cIAP-1和XIAP水平增加，类似于在BRCA1 185delAG细胞系中观察到的情况。综上所述，这些数据表明BRCA1 185delAG突变与半胱天冬酶介导的凋亡途径改变之间存在直接联系。